Recent clinical evidence has demonstrated that immunotherapy is a powerful therapeutic strategy for cancer. However, the immune suppressive tumor microenvironment (TME) posts immense challenges for such approach. Among many immune tolerance mechanisms associated with tumor progression, lack of appropriate danger signal and strong active immune suppression in TME are chiefly responsible for failure to initiate antitumor immune responses and sustain tumor immune therapy. IL-36?, also known as IL-1F9, is a member of the IL-1 family of cytokines. IL-36? can be induced in tissue lining cells such as keratinocytes, bronchial epithelia, and innate cells such as macrophages and is believed to be an alarmin in the damaged tissues and during bacterial and viral infection. Thus, IL-36? is now believed to serve as an endogenous danger signal, which initiates and enhances inflammation and cell-mediated immune responses in affected tissues. We have found that IL-36? is down-regulated in advanced tumor tissues compared to less malignant tumor tissues in human melanoma and lung cancer, suggesting IL-36? might be involved in limiting tumor progression by providing immune stimulatory signals. We further demonstrated that expression of IL-36? in tumor cells strongly inhibited tumor growth in mice without affecting tumor cell proliferation in vitro. And we have demonstrated that the antitumor effect of IL-36? is dependent on CD8+ T cells and NK cells. We hypothesize that the immunological danger signal IL-36? serves as a new tumor-therapeutic cytokine through enhancing effector functions of type 1 lymphocytes such as Th1 cell, CD8+ T cells and NK cells. Specific Aim 1. We will determine whether precise delivery of IL-36? to established tumors by an IL-36?-armed oncolytic virus promotes local type 1 adaptive antitumor immunity. Specific Aim 2. Determine whether blockade of immune checkpoint regulator Tim-3 synergizes with tumoral expression of IL-36? to reverse tumor immune suppression. Such studies will pave clear pathways for clinical application.